What is the role of blood-brain-barrier regional specificity in the nucleus accumbens?

伏隔核中血脑屏障区域特异性的作用是什么？

• 批准号: 10469330
• 负责人: Iris Haleakala Garcia-Pak
• 金额: $ 3.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469330
• 关键词: Acute; Address; Adult; Affect; Aging; All-Trans-Retinol; Alzheimer' s Disease; Area; Basal Ganglia; Behavior; Biological; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cell Differentiation process; Cell Survival; Cerebellum; Cochlear nucleus; Corpus striatum structure; Development; Developmental Process; Diet; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Drug Addiction; Endothelial Cells; Endothelium; Environment; Equilibrium; Exhibits; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Health system; Heterogeneity; Hippocampus (Brain); Homeostasis; Hypothalamic structure; Immune system; Individual; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Metabolism; Molecular; Mus; Nervous System Physiology; Neuraxis; Neurons; Nucleus Accumbens; Organ; Pathway interactions; Peripheral; Play; Predisposition; Prevalence; Prevention; Property; Psychological reinforcement; Public Health; RXR; Retinoids; Rewards; Role; Self Administration; Sensory; Severities; Signal Transduction; Source; Specific qualifier value; Specificity; Spinal Cord; Stimulus; Tamoxifen; Testing; Thalamic structure; Time; Tissue-Specific Gene Expression; Tissues; Toxin; Traumatic Brain Injury; Tretinoin; Variant; Ventral Striatum; Vitamin A; Work; addiction; brain endothelial cell; cell type; conditional knockout; dietary; extracellular; interest; learned behavior; nervous system disorder; neural circuit; neuropsychiatric disorder; pleasure; receptor; relating to nervous system; single-cell RNA sequencing; therapeutic target

PROJECT SUMMARY/ABSTRACT The blood-brain barrier (BBB) is a term that describes the unique properties of central nervous system (CNS) blood vessels which allow them to stringently regulate the extracellular environment of the surrounding neural tissue. While it is known that different brain regions are made up of diverse cell types and execute distinct functions, it is unknown if the BBB exhibits varied features in functionally distinct regions to regulate specific neural circuits. Since little is known about heterogeneity of the BBB, this project will address this gap in knowledge and pursue the question of whether regional specializations of the blood-brain barrier may regulate local circuit function and behavior. This will identify if the BBB could be targeted to modulate specific behaviors, including reward and addiction. Single cell RNA sequencing revealed that there is significant inter-regional heterogeneity of the BBB via differential gene expression in endothelial cells (ECs). While the canonical BBB genes that contribute to restrictive barrier properties were expressed in ECs across all brain regions, many genes involved in transport, signaling, and metabolism were found to be enriched in ECs of specific brain regions. For instance, Stra6, a transport regulator of retinoids, is remarkably enriched in the nucleus accumbens shell (sNAc) and the ventral cochlear nucleus (VCN) compared to other areas of the brain. The sNAc is particularly of interest because its function in reward and reinforcement learning implicates the region in drug addiction. Due to the prevalence and severity of addiction, it is urgently important to find new targets for treating this major public health issue by asking if the BBB, via Stra6, plays a role in regulating addiction. The proposed study will address this critical need by determining (1) if the regional specificity of Stra6 at the BBB is necessary for the development or adult function of the sNAc, (2) by what molecular mechanisms Stra6 regulates sNAc function, and (3) if Stra6 is required for learning addiction behavior. This proposal will test the hypothesis that Stra6 concentrates retinoids within the sNAc, thereby dynamically regulating dopamine receptor levels and thus the adult function of the sNAc in both spatial learning and addiction. The importance of Stra6 at the BBB will be tested using conditional, EC-specific Stra6 knockout mice to excise Stra6 during development or in adulthood. These aims will also test whether elevating dietary Vitamin A, the source of retinoids, can increase retinoid levels in the absence of Stra6 and rescue sNAc function. The central goals of this proposal are to gain deeper understanding of the BBB’s contribution to brain function, specify mechanisms of addiction, and assess what factors might increase individual susceptibility to drug addiction.

项目概要/摘要 血脑屏障 (BBB) 是一个描述中枢神经系统 (CNS) 独特特性的术语 血管使它们能够严格调节周围神经的细胞外环境 组织。虽然众所周知，不同的大脑区域由不同的细胞类型组成并执行不同的任务 功能，尚不清楚 BBB 是否在功能不同的区域表现出不同的特征来调节特定的 神经回路。由于对 BBB 的异质性知之甚少，该项目将解决这一差距 知识并探究血脑屏障的区域专业化是否可以调节的问题 局部电路功能和行为。这将确定 BBB 是否可以有针对性地调节特定行为， 包括奖励和成瘾。 单细胞 RNA 测序揭示 BBB 存在显着的区域间异质性 内皮细胞（EC）中的差异基因表达。虽然典型的 BBB 基因有助于 限制性屏障特性在所有大脑区域的 EC 中表达，许多基因涉及运输， 发现信号传导和代谢在特定大脑区域的 EC 中丰富。例如，Stra6， 类维生素A的运输调节剂，在伏隔核壳（sNAc）和腹侧显着富集 耳蜗核（VCN）与大脑其他区域的比较。 sNAc 特别令人感兴趣，因为它 奖励和强化学习中的功能表明该区域与毒瘾有关。由于流行和 鉴于成瘾的严重性，迫切需要找到新的目标来治疗这一重大公共卫生问题 通过 Stra6 询问 BBB 是否在调节成瘾方面发挥作用。 拟议的研究将通过确定 (1) Stra6 的区域特殊性是否满足这一关键需求 BBB 对于 sNAc 的发育或成年功能是必需的，(2) Stra6 通过什么分子机制 调节 sNAc 功能，以及 (3) Stra6 是否是学习成瘾行为所必需的。该提案将测试 假设 Stra6 将类视黄醇浓缩在 sNAc 内，从而动态调节多巴胺受体 水平，从而影响成人 sNAc 在空间学习和成瘾方面的功能。 Stra6 的重要性 BBB 将使用有条件的 EC 特异性 Stra6 敲除小鼠在发育过程中切除 Stra6 进行测试 或成年后。这些目标还将测试提高膳食维生素 A（类视黄醇的来源）是否可以 在没有 Stra6 的情况下增加类视黄醇水平并挽救 sNAc 功能。该提案的中心目标是 更深入地了解 BBB 对大脑功能的贡献，明确成瘾机制，以及 评估哪些因素可能会增加个体对毒瘾的易感性。